Cortical spreading depolarizations induced by surgical field blood in a mouse model of neurosurgery

Abstract

OBJECTIVECortical spreading depolarization (CSD) has been linked to poor clinical outcomes in the setting of traumatic brain injury, malignant stroke, and subarachnoid hemorrhage. There is evidence that electrocautery during neurosurgical procedures can also evoke CSD waves in the brain. It is unknown whether blood contacting the cortical surface during surgical bleeding affects the frequency of spontaneous or surgery-induced CSDs. Using a mouse neurosurgical model, the authors tested the hypothesis that electrocautery can induce CSD waves and that surgical field blood (SFB) is associated with more CSDs. The authors also investigated whether CSD can be reliably observed by monitoring the fluorescence of GCaMP6f expressed in neurons.METHODSCSD waves were monitored by using confocal microscopy to detect fluorescence increases at the cortical surface in mice expressing GCaMP6f in CamKII-positive neurons. The cortical surface was electrocauterized through an adjacent burr hole. SFB was simulated by applying a drop of tail vein blood to the brain through the same burr hole.RESULTSCSD waves were readily detected in GCaMP6f-expressing mice. Monitoring GCaMP6f fluorescence provided far better sensitivity and spatial resolution than detecting CSD events by observing changes in the intrinsic optical signal (IOS). Forty-nine percent of the CSD waves identified by GCaMP6f had no corresponding IOS signal. Electrocautery evoked CSD waves. On average, 0.67 ± 0.08 CSD events were generated per electrocautery episode, and multiple CSD waves could be induced in the same mouse by repeated cauterization (average, 7.9 ± 1.3 events; maximum number in 1 animal, 13 events). In the presence of SFB, significantly more spontaneous CSDs were generated (1.35 ± 0.37 vs 0.13 ± 0.16 events per hour, p = 0.002). Ketamine effectively decreased the frequency of spontaneous CSD waves (1.35 ± 0.37 to 0.36 ± 0.15 CSD waves per hour, p = 0.016) and electrocautery-stimulated CSD waves (0.80 ± 0.05 to 0.18 ± 0.08 CSD waves per electrocautery, p = 0.00002).CONCLUSIONSCSD waves are detected with far greater sensitivity and fidelity by monitoring GCaMP6f signals in neurons than by monitoring IOSs. Electrocautery reliably evokes CSD waves, and the frequency of spontaneous CSD waves is increased when blood is applied to the cortical surface. These experimental conditions recapitulate common scenarios in the neurosurgical operating room. Ketamine, a clinically available pharmaceutical agent, can block stimulated and spontaneous CSDs. More research is required to understand the clinical importance of intraoperative CSD.

Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury

“…CSDs were recorded when stimulations resulted in an abrupt near-DC/AC ECoG negativity shift, cortical activity depression, hemodynamic response, and change in intrinsic optical signaling of the cortex. To ensure peak systemic drug levels, four additional electrical cortical stimuli were delivered every 15 min, beginning either 30 min following saline or ketamine ( 27 , 84 ), and 45 min following memantine delivery ( 65 ). Topical solutions were added to aCSF applied directly to the exposed cerebral cortex.…”

“…Topical solutions were added to aCSF applied directly to the exposed cerebral cortex. Ketamine was dosed as previously described (100 μM topical and 25 mg/kg, intraperitoneally) ( 27 , 84 ). We used the lowest dose of intraperitoneal memantine (10 mg/kg) at which CSDs were consistently blocked ( 47 , 49 ).…”

“…The excitatory neurotransmitter glutamate is excessively released following TBI and CSDs (26). The N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist ketamine has been shown to suppress CSDs in animals (7,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) and humans (9,(37)(38)(39)(40)(41). Few studies have examined CSDs and ketamine in the context of mild TBI (5,14,15).…”

Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

“…Overall, imaging modalities described here range from low to high invasiveness with thinned skull or cranial window preparations (MPM and fUSI) up to insertion of device into the brain tissue (Miniscope, MFP) that may lead to structural and functional damage to the brain [i.e., tissue inflammation (Dorand et al, 2014 ; Bocarsly et al, 2015 ); brain lesions (Cole et al, 2011 ; Jacob et al, 2018 ); vessels leaking (Chia and Levene, 2009 ); spreading depolarization (Srienc et al, 2019 )] affecting the integrity of NVU/C and inducing confounding effects in the brain cortex. These considerations further highlight the need for appropriate controls or exclusion criterion in studies using these approaches.…”